The long-range goal of this project is to investigate the protective effects of conjugated linoleic acid (CLA) against carcinogenesis. In this dissertation, we demonstrate the mechanisms of CLA action on cell cycle progression and repression of polycyclic aromatic hydrocarbon (PAH)-induced Cyclooxygenase-2 (COX-2) in breast and colon cancer cells. CLA reduced the expression of factors required for G1 to S-phase transition including cyclins D1 and E, and hyperphoshorylated retinoblastoma Rb protein. In contrast, the over-expression of mutant p53 (175Arg to His) in MCF-7 cells prevented the CLA-dependent accumulation of p21 and the reduction of cyclin E levels suggesting that the expression of wild-type p53 is required for CLA-mediated activation of the G1 restriction point. We also report, CLA reduced the expression of COX-2 promoter activity induced by the aromatic hydrocarbon receptor (AhR)-ligand benzo[a]pyrene (B[a]P). Mutagenesis or deletion of potential xenobiotic responsive elements (XREs) within the COX-2 promoter abrogated its ability to be induced by the high affinity AhR-ligand TCDD. In addition, promoter studies using a XRE-dependent CYP1A1 plasmid revealed CLA can inhibit PAH-induced AhR/XRE-driven genes. In both studies, the t10,c12-CLA isomer was more effective than c9,t11-CLA in inhibiting cell proliferation and AhR/XRE-dependent genes. Taken together, these data suggest that the anti-cancerous properties of CLA appear to be a function, at least in part, of the relative content of specific isomers and their 1) ability to elicit a p53 response that leads to the accumulation of pRb and cell growth arrest, and 2) ability to inhibit PAH-induced cyclooxygenase-2 promoter activity through an AhR-dependent mechanism.
| Identifer | oai:union.ndltd.org:arizona.edu/oai:arizona.openrepository.com:10150/193637 |
| Date | January 2005 |
| Creators | Kemp, Michael Quentin |
| Contributors | Romagnolo, Donato F., Romagnolo, Donato F., Howell, Wanda, Houtkooper, Linda, Going, Scott, Winzerling, Joy |
| Publisher | The University of Arizona. |
| Source Sets | University of Arizona |
| Language | English |
| Detected Language | English |
| Type | text, Electronic Dissertation |
| Rights | Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author. |
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